ETS2 (v-ets erythroblastosis virus E26 oncogene homolog 2 (avian))

2008-07-01   Yvonne Buggy , Michael J Duffy 

Drug Safety Research Unit, SO14 0 Southampton, UK (YB); UCD School of Medicine, Medical Science, University College Dublin, Ireland (MJD)




Atlas Image
Exon-Intron structure of human ETS2.


Ets-2 is a functioning gene comprising 10 exons and spanning 19.6 kb of genomic DNA. It encodes three mRNA transcripts: 4.7 kb, 3.6 kb and 2.7 kb, respectively (Watson et al., 1988). This suggests the existence of three functionally distinct proteins, potentially translated from these transcripts.


Structural analysis of the Ets2 promoter has revealed the absence of TATA and CAAT boxes, thus allowing transcription initiation from multiple start sites (Papas et al., 1990a). The first Intron of Ets2 also contains transcriptional initiation sequences, facilitating transcription. These sequences may compensate for the absence of TATA and CAAT sites within the promoter (Begue et al., 1997). The three RNA transcripts are thought to arise from alternative splicing by a number of different promoter polyadenylation signals (Watson et al., 1990). All Ets genes, including Ets2, are characterised by a region of conserved sequence known as the Ets domain (GGAA/T). This comprises an 85 amino acid region which forms the winged helix-turn-helix DNA binding domain (Watson et al., 1990).


Atlas Image
Schematic representation of the Ets2 protein. The pointed domain, the transactivation domain and the Ets DNA binding domain are all shown.


1-469 amino acids
Pointed domain: 87-170 amino acids
DNA binding domain: 363-443 amino acids.
The Ets2 protein consists of 469 amino acids, a pointed domain, a transactivation domain and the Ets DNA binding domain (Watson et al., 1988). The protein is thought to exist in two forms: a 52 kDa, thought to be the full length protein (Watson et al., 1988) and a 54 kDa protein, believed to be a phosphorylated protein (Ma et al.,1996). The Ets2 protein is phosphorylated by Ca2+- dependent mitogenic signaling (Fisher et al., 1989; Fujiwara et al., 1990).


Ets2 has previously been shown to play a role in cell proliferation and differentiation (Kilpatrick et al., 1999). Early studies demonstrated that overexpression of Ets2 results in cellular transformation and proliferation in vitro (Seth et al.,1989). Furthermore, transfection of non-tumourigenic cell lines with Ets2 results in increased cell adhesion and enhanced invasiveness. Increased Ets2 expression has been observed in breast (Buggy et al., 2006; Galang et al., 2004), prostate (Foos et al., 2000; Turner et al., 2007b), esophageal (Li et al., 2003) and hepatocellular (Liao et al., 1996) carcinomas.


The Ets2 protein is located in the nucleus.


Ets-2 has a number of important functions defined in mammalian systems. Ets genes are thought to act as positive or negative regulators of gene expression involved in various biological processes (Papas et al., 1989; Sapi et al., 1998). Ets-2 is thought to be involved in the regulation of cell proliferation and differentiation in certain cell types (Kilpatrick et al., 1999). In T-cells, Ets-2 expression is induced upon mitogenic stimulation (Bhat et al., 1987). It has been demonstrated that Ets-2 overexpression in myeloid progenitor cells stimulates the development of mature macrophages (Aperlo et al., 1996). Yamamoto et al., showed that deleting the Ets-2 gene in mice resulted in growth retardation and often embryonic death (Yamamoto et al.,1998). This may be due to a disruption in the transcriptional regulation of the epidermal growth factor and transforming growth factor-BETA.
Ets-2 expression has long been associated with Downs Syndrome. In 1990, Papas et al., identified and mapped two members of the Ets family of transcription factors - Ets-2 and Erg to the portion of chromosome 21 believed to be involved in Downs Syndrome (Papas et al., 1990 b). The Ets-2 gene is found in three copies in partial trisomies associated with the syndrome phenotype (Sacchi et al., 1988).
In the liver, Ets-2 expression has been associated with hepatic cell regeneration and also with the development of hepatocellular carcinoma (Bhat et al., 1996; Liao et al., 1996). Ets-2 expression has also been found in 30 % of rheumatoid arthritis patients (Sun et al., 2001). Ets-2 expression was reported in the synovial cells, suggesting an intrinsic activation mechanism of this immediate early gene in the disease process (Dooley et al., 1996).
A distinct role for Ets-2 in malignant transformation has been established. Seth et al., demonstrated that Ets-2 expression in NIH3T3 cells stimulates growth in the absence of serum growth factors (Seth et al., 1989). This group also showed that cell lines producing high levels of Ets-2 were capable of proliferating in the absence of serum. The Ets-2 transformed cells also exhibited anchorage-independent cell growth in agar suspension and tumourigenesis in nude mice. This study provides the first evidence of the transforming ability and mitogenic activity of Ets-2. Similar findings have been obtained by Sapi et al., using BT20 breast carcinoma cells (Sapi et al., 1998). Using these cells, colony formation was abolished following transfection with a dominant negative construct of Ets-2. Induction of Ets-2 has also been shown to be necessary for thyroid cell transformation (Sapi et al., 1998).

Implicated in

Entity name
Human malignancies
A growing number of human malignancies have been associated with Ets2 overexpression. Early studies have demonstrated overexpression of Ets2 results in cellular transformation (Seth et al., 1989). Ets2 has been shown to act as both a negative and positive regulator of gene expression in biological processes, including metastasis, angiogenesis, tissue remodeling and apoptosis (Papas et al., 1990a).
Entity name
Breast Cancer
Deregulation of Ets2 has been shown in human breast cancer (Turner et al., 2007a). Buggy et al., showed that both Ets2 mRNA and protein are overexpressed in human breast cancer compared with normal breast tissue (Buggy et al., 2006). Multiple studies in animal models and cell lines suggest that Ets2 is causally involved in breast cancer formation and progression (Buggy et al., 2006; Watabe et al., 1998). Transfection of the non-tumourigenic immortalized MCF-12A breast cancer cells with Ets2 resulted in serum growth factor independent proliferation, growth in soft agar and enhanced invasiveness (Sapi et al., 1998). In addition, Ets2 plays an important regulatory role in controlling expression of the breast tumour promoting protein, parathyroid hormone-related protein (Lindemann et al., 2003).
Entity name
Esophageal Carcinoma
Overexpression of Ets2 has been observed in human esophageal carcinoma (Li et al., 2003). Compared with normal tissue expression of both Ets2 mRNA and protein are upregulated in tumour tissue, suggesting a role in the pathology of esophageal carcinoma.
Entity name
Prostate Cancer
Increased expression of Ets2 has been shown in human prostate cancer (Foos et al., 2000; Turner et al., 2007b). Inhibition of Ets2 by antisense oligonucleotides or dominant negative constructs reduces anchorage-independent growth of prostate cancer cells, significantly reduces the ability of cells to form colonies in soft agar and reduces tumour formation in nude mice. Furthermore, Ets2 has been associated with the transcriptional upregulation of uPA and matrix metalloproteinases (Man et al., 2003; Trojanowska, 2000), which are associated with prognosis in prostate cancer.


Pubmed IDLast YearTitleAuthors
89433401996Constitutive c-ets2 expression in M1D+ myeloblast leukemic cells induces their differentiation to macrophages.Aperlo C et al
94953151997Identification of a second promoter in the human c-ets-2 proto-oncogene.Bègue A et al
34722021987Temporal and tissue-specific expression of mouse ets genes.Bhat NK et al
163802482006Ets2 transcription factor in normal and neoplastic human breast tissue.Buggy Y et al
86601031996Constitutive expression of c-fos and c-jun, overexpression of ets-2, and reduced expression of metastasis suppressor gene nm23-H1 in rheumatoid arthritis.Dooley S et al
25165001989c-ets-2 and the mitogenic signal pathway.Fisher RJ et al
111147282000Altered Ets transcription factor activity in prostate tumor cells inhibits anchorage-independent growth, survival, and invasiveness.Foos G et al
21375531990Phosphorylation of the ETS-2 protein: regulation by the T-cell antigen receptor-CD3 complex.Fujiwara S et al
146627582004Changes in the expression of many Ets family transcription factors and of potential target genes in normal mammary tissue and tumors.Galang CK et al
103770391999Transcription factors Ets1, Ets2, and Elf1 exhibit differential localization in human endometrium across the menstrual cycle and alternate isoforms in cultured endometrial cells.Kilpatrick LM et al
125324322003Overexpression of ETS2 in human esophageal squamous cell carcinoma.Li X et al
86204441996Expression of the c-jun, jun-B, ets-2 and liver regeneration factor-1 (LRF-1) genes during promotion and progression of rat liver carcinogenesis in the resistant hepatocyte model.Liao DZ et al
126280052003Ets2 and protein kinase C epsilon are important regulators of parathyroid hormone-related protein expression in MCF-7 breast cancer cells.Lindemann RK et al
89589541996A novel ets-2-related nuclear factor is involved in transcriptional activation of the human interleukin-12 p40 gene promoter in response to interferon-gamma and LPS stimulation of monocytic cells.Ma X et al
146124052003Ets2-dependent stromal regulation of mouse mammary tumors.Man AK et al
22475051990The ETS family of genes: structural analysis, gene products, and involvement in neoplasia and other pathologies.Papas TS et al
26592781989The ets family of genes: molecular biology and functional implications.Papas TS et al
21499581990ETS family of genes in leukemia and Down syndrome.Papas TS et al
32672121988The ETS genes on chromosome 21 are distal to the breakpoint of the acute myelogenous leukemia translocation (8;21).Sacchi N et al
95004661998Ets-2 transdominant mutant abolishes anchorage-independent growth and macrophage colony-stimulating factor-stimulated invasion by BT20 breast carcinoma cells.Sapi E et al
98799941998ETS2 function is required to maintain the transformed state of human prostate cancer cells.Sementchenko VI et al
28133601989c-ets-2 protooncogene has mitogenic and oncogenic activity.Seth A et al
121822272002ETS proteins and MMPs: partners in invasion and metastasis.Singh S et al
112486612001Messenger-RNA expression of matrix metalloproteinases, tissue inhibitors of metalloproteinases, and transcription factors in rheumatic synovial cells under mechanical stimuli.Sun HB et al
111753622000Ets factors and regulation of the extracellular matrix.Trojanowska M et al
176613552007Defining ETS transcription regulatory networks and their contribution to breast cancer progression.Turner DP et al
173081022007Prostate-derived ETS factor is a mediator of metastatic potential through the inhibition of migration and invasion in breast cancer.Turner DP et al
96394041998The Ets-1 and Ets-2 transcription factors activate the promoters for invasion-associated urokinase and collagenase genes in response to epidermal growth factor.Watabe T et al
19645971990Molecular analysis of the ets genes and their products.Watson DK et al
28471451988Mammalian ets-1 and ets-2 genes encode highly conserved proteins.Watson DK et al
95730481998Defective trophoblast function in mice with a targeted mutation of Ets2.Yamamoto H et al

Other Information

Locus ID:

NCBI: 2114
MIM: 164740
HGNC: 3489
Ensembl: ENSG00000157557


dbSNP: 2114
ClinVar: 2114
TCGA: ENSG00000157557


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Dorso-ventral axis formationKEGGko04320
Dorso-ventral axis formationKEGGhsa04320
HTLV-I infectionKEGGko05166
HTLV-I infectionKEGGhsa05166
Ras signaling pathwayKEGGhsa04014
Cellular responses to stressREACTOMER-HSA-2262752
Cellular SenescenceREACTOMER-HSA-2559583
Oncogene Induced SenescenceREACTOMER-HSA-2559585


Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA443622Carcinoma, Non-Small-Cell LungDiseaseClinicalAnnotationassociatedPD31616045


Pubmed IDYearTitleCitations
155726962004Ras/mitogen-activated protein kinase signaling activates Ets-1 and Ets-2 by CBP/p300 recruitment.90
228262362012Transcription factors ETS2 and MESP1 transdifferentiate human dermal fibroblasts into cardiac progenitors.79
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
263896652015Non-canonical NF-κB signalling and ETS1/2 cooperatively drive C250T mutant TERT promoter activation.61
185866742008Ets2 maintains hTERT gene expression and breast cancer cell proliferation by interacting with c-Myc.49
206712292010Ets-1 and Ets-2 regulate the expression of microRNA-126 in endothelial cells.48
201451332010An ets2-driven transcriptional program in tumor-associated macrophages promotes tumor metastasis.46
236599682013ETS2 mediated tumor suppressive function and MET oncogene inhibition in human non-small cell lung cancer.46
157886562005Associations and interactions between Ets-1 and Ets-2 and coregulatory proteins, SRC-1, AIB1, and NCoR in breast cancer.42
158061512005ERK phosphorylation is linked to VEGFR2 expression and Ets-2 phosphorylation in breast cancer and is associated with tamoxifen treatment resistance and small tumours with good prognosis.39


Yvonne Buggy ; Michael J Duffy

ETS2 (v-ets erythroblastosis virus E26 oncogene homolog 2 (avian))

Atlas Genet Cytogenet Oncol Haematol. 2008-07-01

Online version: